Lack of selectivity of chemotherapeutic agents is a major problem in cancer treatment. Because highly toxic compounds are used in cancer chemotherapy, it is typically associated with severe side effects. Drug concentrations that would completely eradicate the tumor cannot be reached because of dose-limiting side effects such as gastrointestinal tract and bone marrow toxicity. In addition, tumors can develop resistance against anticancer agents after prolonged treatment. In modem drug development, targeting of cytotoxic drugs to the tumor site can be considered one of the primary goals.
A promising approach to obtain selectivity for tumor cells or tumor tissue is to exploit the existence of tumor-associated enzymes. A relatively high level of tumor-specific enzyme can convert a pharmacologically inactive prodrug to the corresponding active parent drug in the vicinity of the tumor. Via this concept a high concentration of toxic anticancer agent can be generated at the tumor site. All tumor cells may be killed if the dose is sufficiently high, which may decrease development of drug resistant tumor cells.
There exist several enzymes that are present at elevated levels in certain tumor tissues. One example is the enzyme β-glucuronidase, which is liberated from certain necrotic tumor areas. Furthermore, several proteolytic enzymes have been shown to be associated with tumor invasion and metastasis. Several proteases, like for example the cathepsins and proteases from the urokinase-type plasminogen activator (u-PA) system are all involved in tumor metastasis. The serine protease plasmin plays a key role in tumor invasion and metastasis. The proteolytically active form of plasmin is formed from its inactive pro-enzyme form plasminogen by u-PA. The tumor-associated presence of plasmin can be exploited for targeting of plasmin-cleavable prodrugs.
In this invention a new technology is disclosed that can be applied to prepare improved prodrugs or conjugates for targeting drugs to disease-related or organ-specific tissue or cells, for example tumor-specific prodrugs. This technology can furthermore find application in (non-specific) controlled release of compounds, with the aim of facilitating release of the parent moiety. The present invention is deemed to be applicable to all drugs that need to be delivered at a specific target site where a specific disease-related biomolecule can convert the prodrug into the drug or induce conversion of the prodrug into the drug.